Chiropractic spinal manipulative therapy for acute neck pain: A 4-arm clinical placebo randomized controlled trial. A prospective study protocol

Introduction Neck pain poses enormous individual and societal costs worldwide. Spinal manipulative therapy and Non-Steroidal Anti-Inflammatory Drug treatment are frequently used despite a lack of compelling efficacy data. This protocol describes a multicentre 4-arm, clinical placebo randomized controlled trial (RCT), investigating the efficacy of chiropractic spinal manipulative therapy (CSMT) versus sham CSMT, ibuprofen, and placebo medicine for acute neck pain. This superiority study will employ parallel groups, featuring a 1:1:1:1 allocation ratio. Material and methods We will randomize 320 participants equally into four groups: CSMT, sham CSMT, ibuprofen, or placebo medicine. CSMT groups are single-blinded, while the medicine groups are double-blinded. Data will be collected at baseline (Day 0), during treatment and post-treatment. The primary endpoint will assess the difference in mean pain intensity from Day 0 to Day 14 on a numeric rating scale 0–10; the CSMT group is compared to sham CSMT, ibuprofen, and placebo medicine groups, respectively. Secondary endpoints will assess mean pain intensity and mean duration at different time points, and adverse events, blinding success, and treatment satisfaction, including comparison between ibuprofen and placebo medicine. Power calculation is based on a mean neck pain rating of 5 at Day 0, with standard deviation of 1 in all groups. Mean pain reduction at Day 14 is expected to be 60% in the CSMT group, 40% in sham CSMT and ibuprofen groups, and 20% in the placebo medicine group. A linear mixed model will compare the mean values for groups with corresponding 95% confidence intervals. P values below 0.017 will be considered statistically significant. All analyses will be conducted blinded from group allocation. Discussion This RCT aims towards the highest research standards possible for manual-therapy RCTs owing to its two placebo arms. If CSMT and/or ibuprofen proves to be effective, it will provide evidence-based support for CSMT and/or ibuprofen for acute neck pain. Trial registration ClinicalTrials.gov identifier: NCT05374057. EU Clinical Trials Register: EudraCT number: 2021-005483-21.


Background
The Global Burden of Disease study ranks musculoskeletal neck pain as the most common disability worldwide (1).This study will highlight and validate chiropractic manual-therapy for acute neck pain.The applied methodology of the study will aim towards the highest research standards possible for manual-therapy randomized controlled trials (RCTs), thus avoiding typical methodological shortcomings from previous manual-therapy studies, including lack of a placebo comparison group.
Our study aims to establish the efficacy of chiropractic manual-therapy in the management of acute neck pain compared to other relevant treatment options, in order to enhance evidence-based clinical practice.
The Global Burden of Disease study states that musculoskeletal disorders, more specifically lower back and neck pain in the period 1990-2015, were the leading cause of non-fatal disability in almost all age groups (2, 3).The point prevalence estimate of neck pain was 4.9-7.6%(4,5).In other words, >400 000 Norwegians were suffering from neck pain on any given day per 3 rd quarter in 2021.The total cost to society is unknown; however, a recent review estimated that the annual spending on personal health care and public health for low back and neck pain combined was USD 87.6 billion in the US alone (6).The World Health Organization recently acknowledged that musculoskeletal health conditions contribute greatly to disability across the life-course in all regions of the world.As much as 46% of sickness absence and 33% of disability pensions are directly related to musculoskeletal disorders (7,8).

Introduction
Neck pain is a frequent and episodic condition Episodes of neck pain of varying duration are very common in the general population, as up to 50% of adults experience neck pain within one year, and the recurrence of neck pain is frequent (12,13).

Spinal manipulation is one method to treat neck pain
Neck pain is the second most common complaint treated by chiropractors, after lower back pain (14,15).More than 90% of Norwegian chiropractors use various manipulation-and/or mobilization techniques, often combined with soft tissue techniques, exercise modalities, and general advice (16).Spinal manipulative therapy (SMT) is defined as a passive controlled manoeuvre that uses a directional high-velocity low amplitude (HVLA) thrust directed at a specific joint past the physiological range of motion without exceeding the anatomical limit (17).SMT may relieve neck pain by stimulating neural inhibitory systems at different spinal cord levels, through activation of various central descending inhibitory pathways (18)(19)(20)(21)(22)(23).However, the physiological mechanisms of pain relief are not fully understood, and contextual factors need to be identified (24).

Evidence for effect of spinal manipulation for neck pain
A Cochrane review included 51 trials (2,920 participants) assessing manual-therapy for neck pain (15).Eighty percent (41/51) of the studies were found to be of very low or low quality.Thus, uncertainty regarding the effectiveness of manual-therapy for neck pain remains.

Methodological issues
The methodological quality of manual-therapy RCTs for a range of musculoskeletal disorders is frequently criticised for being too low.Furthermore, the lack of blinding is regarded as a major shortcoming.Manual-therapy RCTs cannot be double-blinded as in pharmacological RCTs, since the practitioner providing the interventions in a manual-therapy study cannot be blinded.It is generally recommended that the placebo intervention should resemble the active treatment in terms of the procedure, treatment frequency and the time spent with the patient, to allow for similar expectations in both groups (25).However, an appropriate placebo for manual-therapy still lacks consensus amongst clinical and academic experts (26).For this reason, previous manual-therapy studies were pragmatic and/or used "no treatment" as the control group.Our research group invented and validated CSMT sham intervention in two RCTs (27,28).The results indicated that it was possible to conduct a chiropractic sham-controlled manual-therapy RCT, where the study participants were blinded throughout the study period, with 12 interventions over 3 months.The manual placebo method has since been used with success in >30 international clinical trials (29)(30)(31)(32)(33). Thus, manual-therapy RCTs can be single-blinded.

Scientific rationale for the proposed study
Acute neck is very common in the general population and often cause disability of shorter or longer time periods.Unfortunately, the efficacy of CSMT and the efficacy of NSAIDs on acute neck pain is unknown (15).This 4-armed RCT will likely provide evidence for the efficacy of CSMT as well as NSAIDs.
Our study will compare CSMT to a credible and validated CSMT sham manipulation.Two pharmacological arms are also to be introduced, in the form of an ibuprofen medication and a placebo medication treatment arm.The 4-armed placebo-controlled RCT will assess the efficacy in the following four treatment groups: 1) CSMT 2) CSMT sham manipulation (placebo) 3) Ibuprofen 600 mg 4) Placebo medication.
Patient, health care system and research benefits and risk Should our study find that chiropractic manual-therapy and medication treatments are effective, then our study will provide evidence-based data for non-pharmacologic and pharmacological treatment.
Patients' benefits -Those who prefer chiropractic manual-therapy -Those who do not respond-, prefer to avoid-, and/or do not tolerate ibuprofen -Those who do not respond to physiotherapy and/or other manual treatment -Relieve the burden of pain, speed up recovery, reduce sick leave Health care system benefits -Reduce costs of inert treatments, reduce sick leave, reduce referrals to 2 nd and 3 rd line health care, reduce referrals to image diagnostics, and filling knowledge gaps among chiropractors, other manual therapists and physicians.
Research benefits -The methodology of blinding in a manual-therapy RCT by including a valid CSMT sham manipulation arm is of importance to establish efficacy with certainty.Additionally, it can be applied in future manual-therapy RCTs.
Patients' risk -Real and sham CSMT side effect are muscle soreness -Ibuprofen side effects, i.e. nausea, abdominal pain, dyspepsia, allergic reactions, headache and skin rash.

Benefit-risk ratio
The overall benefit-risk ratio is in favour of CSMT and ibuprofen treatment, as the probability for treatment effect by far exceeds the very low risk for serious adverse events.

Hypothesis, aims and study approach
Hypothesis CSMT is effective in the management of acute neck pain, more so than CSMT sham manipulation, Ibuprofen medication, and placebo medication.

Short term aims
Relief of neck pain.Inspire towards higher scientific methodological quality of manual-therapy RCTs by specifically including a placebo intervention arm.

Long term aims
Relief of neck pain.Provide evidence-based data for non-pharmacological and pharmacological treatment.
Study approach a) Design a 4-armed multi-center practice-based placebo-controlled RCT on the effect of chiropractic manual-therapy for acute neck pain b) Conduct the RCT c) Publish results in high impact scientific journals d) Provide evidence-based results for health care providers e) Present results to the public including national and international media f) Present results to professionals at national and international meetings and congresses

Methodology
The project group has finalised the study protocol and will obtain the necessary approvals before initiation, see the ethical consideration section below for details.The PostDoc has recruited chiropractors for the project and will together with the PhD student and the study group thoroughly prepare them for the rigorous methodological approach through a workshop.The PhD student will monitor the clinical trial throughout the data collection period and ensure participants and interventional therapist protocol compliance.Data analysis will consist of a collaboration between the PhD student, project leader, supervisors, PostDoc and statistician, with the latter as a key figure in power calculation and the data analysis.The PhD student will draft publications.For specific time points, see progression and activity plan.
Our research design selection was based on our previous experience that it is possible to conduct chiropractic placebo-controlled RCTs (34).It will not possible to blind the manual therapist, i.e., the chiropractor.However, the two pharmacological arms will be double-blinded.The study participants, the monitor (PhD student) and the statistician are all to be blinded.

Study design
A total of 17 chiropractors from larger Norwegian cities have been recruited (page 3) and will be expanded with up to 8 chiropractors, distributed by gender and geography, equalling 1.6-3.0% of all chiropractors registered in Norway in 2016, according to the Norwegian Chiropractic Association.Each chiropractor is assigned to a chiropractor ID number used in the TSD database and when analysing data.The chiropractor know his/hers own ID number and the study group also know the ID number for each chiropractor.The ID numbers is omitted from page 3, the chiropractor list, as others can retrieve this document.Thus, it is not possible to identify personal data from the participating chiropractors in the TSD database, i.e. deidentified (avidentifisert).The study participants presenting to each chiropractor will be block-randomized into one of four study groups based on a computergenerated algorithm.Each chiropractor will include 16 participants, four into each arm.A total of 320 participants will be enrolled in the RCT, within 12 months (see participant's flow diagram).
Randomization Each chiropractor will receive four sets each consisting of four concealed envelopes.Each set of four concealed envelopes contain one allocation to each of the four arms.The randomization log has was conducted by a statistician.The consecutive participant will draft a concealed envelop, and then hand it over to the chiropractor, since the participant is not allowed to see if whether it is real or sham chiropractic to be received.If the participant is randomized to medicine, neither the chiropractor nor the participant will know whether the participant receive ibuprofen or placebo, since Kragerø tablet production will package the medicine according to the randomization log provided by the statistician.The participant randomization ID number is filed in the TSD database, while no personal data are filed, i.e. deidentified (avidentifisert).The chiropractors keep a secure list of participant's name, mobilphone and e-mail address and ID numbers under lock, and the PhD student also have this list, as she has to email the participants when they need to fill in the different questionnaires during the study.She will keep this list under lock in the Trial Master File.To ascertain the questionnaires Bank ID are used, but the Bank ID data are not filed.The participants ID number connects questionnaires from each participant.
Inclusion criteria 1. Eligible participants are between the age of 18 and 59 years old 2. Acute non-radicular neck pain, i.e., grade 1 or 2 according to the classification by the Bone and Joint Decade 2000-2010 Task Force on neck pain (35).3. Onset of the present episode ≤2 weeks prior to the 1 st chiropractic visit.4. Moderate, severe or very severe pain intensity, i.e., ≥4, on a numeric rating scale (NRS) 0-10. 5. Pain free for at least four consecutive weeks prior to the present pain episode.6.Not treated by a chiropractor during the past 6 months.7. Participants must accept not to seek other manual and/or pharmacological treatments for their acute neck pain during the intervention period.8. Non-pregnant women.Women in doubt shall have a negative fertility test before inclusion.

Excluded from analysis Excluded from analysis Excluded from analysis
Akershus University Hospital, University of Oslo,(withreasons)Nordbyhagen, Norway(withreasons).The majority of(withthe reasons)project (n=20) (n=20) (n=20) group work at Faculty of Medicine, Institute of Health and Society, University of Oslo, Norway.All interviews, assessments and interventions will be conducted by experienced chiropractors at Norwegian chiropractic clinics.The Ibuprofen and the placebo medication group will receive medication at the chiropractic clinic that recruited the participant.

Clinical trial
The clinical trial will adhere to the protocol, the ICH-GCP and Norwegian regulations for clinical trials.(Clinical Trials are mainly regulated by international and national laws, and the European Directive 2001/20/EC, which is fully implemented in the Norwegian Regulation relating to Clinical Trials on Medicinal Products for Human Use.) Reference safety information (RSI) is the SmPC for ibuprofen 600 mg.
The clinical trials consist of three stages: Run-in, intervention (treatment) and follow-up.The CSMT, and the CSMT sham manipulation, group 1 and 2 will include five intervention sessions over 10-12 days, i.e., three sessions the 1 st week and two sessions the 2 nd week unless they recovered or experienced a serious adverse event (AE) during this period.The Ibuprofen and the placebo medication, group 3 and 4 will receive a package with 36 tablets, i.e., 600 mg ibuprofen or placebo to be taken three times per day for 12 days.

Interventions
The first active treatment will consist of CSMT (31), i.e., a specific contact, high-velocity, lowamplitude, spinal thrust manipulation directed to spinal biomechanical dysfunction in the cervical and/or thoracic spinal column, as diagnosed by standard chiropractic tests, in accordance with their clinical judgment.No additional co-interventions or specific advice apart from reassurance of "business as usual" and encourage of normal activities will be given to this group during the trial period, in accordance with practice guidelines.
The CSMT sham intervention group will consist of CSMT sham manipulation, i.e., a broad nonspecific contact, low-velocity, low-amplitude sham push manoeuvre in a non-therapeutic directional line (34,39,40).All the non-therapeutic contacts will be performed outside of the spinal column with adequate joint slack and without soft tissue pre-tension, so that joint cavitations do not occur.
No additional co-interventions or specific advice apart from reassurance of "business as usual" and encourage of normal activities will be given to this group during the trial period.
The Ibuprofen and placebo medication groups will receive 36 tablets ibuprofen 600 mg or 36 tablets placebo (three daily administrations for 12 days) (41,42).All interventions will be free of charge for the included participants.No additional co-interventions or specific advice apart from reassurance of "business as usual" and encourage of normal activities will be given to this group during the trial period.
Participants in all four groups who do not experience spontaneous improvement, will after study completion (after 6 months follow-up) be offered a free of charge chiropractic assessment and treatment, if necessary, at the location they were first randomized, for up to five treatment sessions.
Similarly, participants with a relapse of neck pain during the follow-up period will also be offered a second round of the same intervention, free of charge after 6 months follow-up.

Ethical considerations
The study is approved by the Norwegian Regional Committee for Medical Research Ethics (REK) (REK: 2020/28498).The study has been approved by Personvernombudet, the Norwegian Social Science Data Services at Akershus University Hospital, Lørenskog, Norway, and the Norwegian Medicines Agency (EUDRA CT NR. 2021-005483-21), prior to initiation of the study.The declaration of Helsinki is followed.All data will be deidentified (avidentifisert) by the use of ID number for both chiropractors and participant.To ascertain the questionnaire Bank ID is used, but the Bank ID data are not filed.The participants ID number connects questionnaires from each participant.Data will be stored electronically at Services for Sensitive Data (TSD), University of Oslo for five years.Insurance is provided through "The Norwegian System of Compensation to Patients" (NPE) and through the Legemiddelverkets ansvarsforsikringen, Norwegian Medicines Agency.A stopping rule was defined for withdrawing participants from this study in accordance with recommendations in the CONSORT extension for Better Reporting of Harms.If a participant reports to their chiropractor or research staff a severe AE, he or she will be withdrawn from the study and referred to their general practitioner or hospital emergency department depending on the nature of the event.

Dissemination
The outcomes of the study will be published in peer-reviewed international scientific journals in accordance with the CONSORT 2010 Statement.The outcomes will be published regardless of whether they are positive, negative, or inconclusive.A written lay summary of the study outcomes will be available for the participants on request.The study outcomes will also be presented as posters or oral presentations at national and international meetings and congresses.

Analyses
All data recordings will be obtained electronically through TSD and analysed by a statistician, blinded for the participant's group allocation.Baseline demographic and clinical characteristics will be recorded at the 1 st chiropractic visit and be tabulated as means and standard deviations (SD) for continuous variables, and proportions and percentages for categorical variables.Primary and secondary end-points will be presented using suitable descriptive statistics in each group and for each time point.The comparison of groups will be performed by a linear mixed model with fixed effects for time, group and interaction between the two.Random effects for participants nested within chiropractors will be included.As primary analysis, change in primary end-point from baseline to day 14 will be compared between group 1 and group 2, group 1 and group 3, and group 1 and group 4. As secondary analyses, comparisons of trend from baseline through follow-up between group 1 and group 2, group 1 and group 3, group 1 and group 4, will be performed for primary and secondary endpoints.Moreover, stratified analyses will be performed by estimating the same model with additional fixed effects for sex and age and the interactions between those two and the group and time variables.

Data recording
Onset, numbers of days, duration and neck pain intensity will be recorded at the first chiropractic visit (baseline) prior to randomization, and at 1, 4-, 8-, 12-and 24-weeks post-treatment.Sick leave due to the neck pain episode or for any other reasons will also be monitored throughout the study period.
Additionally, days, intensity and duration of neck pain will be measured every day for 14 days.
The specific wording of these three questions will be.1. "On average, how strong was your neck pain today, on an NRS scale from 0 to 10, where 0 is no pain and 10 is unbearable pain?" 2. "At worst, how strong was your neck pain today, on an NRS scale from 0 to 10, where 0 is no pain and 10 is unbearable pain?" 3. "How many hours did you have neck pain during the past 24 hours?"RAND-12 and Neck Disability Index questionnaires will be recorded at 1 st chiropractic visit (baseline) prior to randomization, at day 14 and at follow-up weeks 12 and 24 (43,44).

Schedule of activities/events Baseline Chiropractor demographics
Investigate efficacy of CSMT and NSAIDs on impact on health and effect on neck disability.

Primary end-point
The primary end-point will be defined as the mean pain intensity on a NRS 0-10.The primary analysis will assess the difference in mean pain intensity change from baseline to day 14 after baseline between group 1 and group 2, group 1 and group 3, and group 1 and group 4.
Secondary end-points 1. Mean pain intensity (NRS 0-10) change from baseline to day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 in the treatment period, and from baseline to day 7, 28, 56, 84 and 168 post-treatment, respectively, and comparison between group 1 and group 2, group 1 and group 3, and group 1 and group 4. 2. Mean duration (hours) of neck pain change from baseline to day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14 after baseline, day 7, 28, 56, 84 and 168 post-treatment, respectively, and comparison between group 1 and group 2, group 1 and group 3, and group 1 and group 4. 3. Mean number of days with neck pain per week from the treatment period (14 days) to the periods; day 1-7, 22-28, 50-56, 78-84 and 162-168 post-treatment, respectively, and comparison between group 1 and group 2, group 1 and group 3, and group 1 and group 4. 4. Proportions of participants with mean daily pain intensity reduction of ≥50%, ≥75% and 100% from baseline to day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14 in the treatment period, and from baseline to day 7, 28, 56, 84 and 168 post-treatment, respectively, and comparison between group 1 and group 2, group 1 and group 3, and group 1 and group 4. 5. Proportions of participants with mean duration (hours) reduction of ≥50%, ≥75% and 100 from baseline to day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14 in the treatment period, and from baseline to day 7, 28, 56, 84 and 168 post-treatment, respectively, and comparison between group 1 and group 2, group 1 and group 3, and group 1 and group 4. 6. Proportions of participants with mean reduction of number of days with neck pain per week of ≥50%, ≥75% and 100% from the 14 days treatment period, to the periods day 1-7, 22-28, 50-56, 78-84 and 162-168 post-treatment, respectively, and comparison between group 1 and group 2, group 1 and group 3, and group 1 and group 4. 7. Improvement in RAND-12 score from baseline to day 14 after baseline, day 84 and 168 posttreatment, respectively, comparison between group 1 and group 2, group 1 and group 3, and group 1 and group 4. 8. Improvement in Neck Disability Index score from baseline to day 14 after baseline, day 84 and 168 post-treatment, respectively, and comparison between group 1 and group 2, group 1 and group 3, and group 1 and group 4. 9. AE analysis of group 1, group 2, group 3 and group 4, and comparison between group 1 and group 2, group 1 and group 3, and group 1 and group 4. 10.Analysis of patients' blinding on NRS 0-10 in relation to receiving real CSMT (0 absolutely unsure and 10 absolutely sure that real CSMT was received), irrespectively, whether the patient receive sham or real CSMT, analysis of group 1 and group 2 and comparison between group 1 and group 2. 11.Analysis of patients' blinding on NRS 0-10 in relation to receiving ibuprofen (0 absolutely unsure and 10 absolutely sure that ibuprofen was received), irrespectively, whether the patient receive ibuprofen or placebo medicine, analysis of group 1 and group 2 and comparison between group 1 and group 2. 12. Analysis of patients' and chiropractors' expectations to treatment efficacy on NRS 0-10 (0 no expectation of treatment efficacy and 10 the highest possible expectation to treatment efficacy).13.Analysis of patients' satisfaction to treatment efficacy on NRS 0-10 (0 no satisfaction at all, and 10 the highest possible satisfaction).

Blinding
After each intervention, the participants will complete a de-blinding questionnaire (34).The included chiropractors will complete the same questionnaire post-treatment.

Publication plan
The PhD project stipulates a minimum of three papers published in high impact scientific peer reviewed medical journals.i) Chiropractic spinal manipulative therapy for acute neck pain: a study protocol of a 4armed, randomized placebo-controlled trial.ii) Chiropractic spinal manipulative therapy for acute neck pain: a 4-armed, randomized placebo-controlled trial.iii) Validation of sham manipulation (placebo) in a multi-centre practice-based chiropractic manualtherapy randomized controlled trial.iv) Adverse events in chiropractic spinal manipulative therapy vs. ibuprofen in patients with acute neck pain.A randomized, semi double-blind, multi-centre, placebo-controlled clinical trial.

Plan for activities, visibility and dissemination
The chiropractic PhD student and the PostDoc will participate once or twice per year at National and International meetings and congresses of relevance, and present results.Data will be published in high impact medical journals, in order to diminish the barrier and allow for better professional distribution between the medical and the chiropractic and/or manual-therapy professions.

Plan for implementation and visibility
Our experience with a previous chiropractic RCT for migraine is that it had major interest right after publication (27).This was also true for our review papers (48)(49)(50), prior to the RCT results being published.This was probably due to publication in high impact medical journals and free access to the e-publication.We will pursue the same strategy for this project.

User involvement
The project will be associated with users from Ryggforeningen i Norge, Norway.They will function as discussion partners.When the results of the study are available, they will assist in disseminating the results to patients, patient organizations and healthcare professionals who treat this patient group.This will be conducted through articles in scientific high impact journals, lectures, member magazines and other relevant publications.Ryggforeningen i Norge may also be a driving force to implement the new knowledge from the project quickly.

Innovative and scientific value
This 4-armed manual-therapy RCT will highlight and validate chiropractic manual-therapy and medication for participants with acute neck pain.The study design protects against the many warned biases in manual-therapy RCT.This is to our knowledge the first RCT to include both a manual sham placebo arm as well as a pharmacological placebo arm.The introduction of a validated manual sham placebo arm is a major innovative improvement which lifts manual-therapy RCTs to the level of pharmacological RCTs and makes it possible to evaluate true net effect (34).Studies with unimodal approaches isolate (statistically) the individual effects of SMT better than multimodal approaches do.Assessing the effect of multimodal programs is problematic, because it is difficult to isolate the impact of a specific intervention.Although most cases of acute neck pain, regardless of whether or not they are radicular in nature, will resolve within three months, a substantial proportion of people will continue to experience low-grade symptoms or frequent recurrences (5).Thus, the study has rationalized a triangle of importance for stakeholders between patients'-, health care system-and research benefits.

Limitations
All clinical studies of certain durations have a risk of drop-out.However, this is minimized through the relatively short intervention-and follow-up period.
There is a recruitment risk since patients might have an expectation towards chiropractic treatment and not medication, when seeking care.This will be resolved by adding more recruiting chiropractic clinics.Risk of unsuccessful blinding in the CSMT sham manipulation group due to multicentre study design and ≥20 chiropractors.Nevertheless, the manual placebo has been evaluated in >30 international clinical studies with concealed placebo groups.
Although this is very difficult to control for, we need to acknowledge that known contextual factors might be present and influence the placebo response.
The study will be the first 4-armed manual-therapy and medication RCT that will assess the efficacy of four different intervention groups; 1) CSMT, 2) CSMT sham manipulation, 3) Ibuprofen medication and 4) placebo medication, for patients with acute neck pain.
To our knowledge, this is the first manual-therapy RCT to include two placebo groups.
There is a strong external validity, which improves the generalizability.
The RCT has the potential to provide evidence-based non-pharmacological and pharmacological treatment option for patients with acute neck pain.
Delegation log (Delegereingslogg) 1. Chiropractor recruit and randomize participants in the study.
2. Chiropractor provide participants allocated to medicine with medication.
3. Chiropractor provide manual therapy to participants allocated to manual therapy.4. Chiropractor receive information and manage serious adverse event due to manual therapy.
5. PhD student receive information and manage serious adverse event due to medication along with the project leader (MD).

Exclusion criteria 1 .
Contraindication to ibuprofen a. active peptic ulcer b. gastrointestinal bleeding c. previous repeated episode (≥2 detected events) with peptic ulcer or gastrointestinal bleeding d. previous gastrointestinal bleeding or ulcer using NSAIDs e. hypersensitivity to ibuprofen f. asthma induced by acetylsalicylic acid or other NSAIDs g. urticarial h.rhinitis i. severe heart failure (NYHA class IV) j. renal failure (glomerulus infusion <30 ml/min), 2. Ingestion of NSAIDs 3. Prescription opioids within ≤14 days 4. Ingestion of any analgesics within ≤24 hours prior to baseline 5. On prescribed antidepressant.6.Major psychiatric disorder.6. Pregnancy or intension to be pregnant 7. Contraindication to SMT. 8. Signs of spinal radiculopathy including progressive neurological deficit 9. Upper cervical spine instability (positive Sharp-Purser test)(36) 10.Previous fracture in the cervical and/or thoracic spine 11.Previous cervical spine surgery, 12. Recent (<6 months) severe physical trauma to the head, neck or thoracic spine within the previous 6 months 13.Concomitant low back pain with moderate, severe or very severe pain intensity (≥4 on a NRS) 14.Current chronic pain (defined as ≥3 months duration) 15.Rheumatoid arthritis 16.Recent (<2 weeks) acute respiratory infection with fever 17.Any presence of ischemic symptoms upon examination 18. Horner's syndrome 19.Medical history of arterial anomalies 20.History of connective tissue disorder 21.Familial history of cervical artery dissection 22.Other vascular disorders (37) 23.Inability to understand instructions given in the Norwegian language 24.Inability to fill out digital questionnaires 25.Other reasons to exclude the patient as deemed necessary by the chiropractor.
6. PhD student fill in SUSAR and sent it to SLV.